Comparison of aggregated exposure to perfluorooctanoic acid (PFOA) from diet and personal care products with concentrations in blood using a PBPK model - Results from the Norwegian biomonitoring study in EuroMix.

BACKGROUND: Per- and polyfluoroalkyl substances (PFAS) constitute a large group of compounds that are water, stain, and oil repellent. Numerous sources contribute to the blood levels of PFAS in the European population. The main contributor for perfluorooctanoic acid (PFOA) is food, house dust, consumer products and personal care products (PCPs). OBJECTIVES: The purpose of the present work is to calculate the dietary and dermal external exposure to PFOA, estimate the aggregated internal exposure from diet and PCPs using a PBPK model, and compare estimates with measured concentrations. METHODS: Detailed information on diet and PCP use from the EuroMix study is combined with concentration data of PFOA in food and PCPs in a probabilistic exposure assessment. A physiologically based pharmacokinetic model (PBPK) was further refined by incorporating a dermal exposure pathway, and changes in the kidney and faecal excretion. RESULTS: The aggregated internal exposure using the PBPK model shows that the major contributor to the internal exposure is diet for both males and females. The estimated internal exposure of PFOA for the EuroMix population was in the same range but lower than the measured blood concentrations using the lower bound (LB) external exposure estimates, showing that the LB estimates are underestimations. For seven females the internal exposure of PFOA were higher from PCPs than from diet. CONCLUSION: PCPs and diet contributed in the same range to the internal PFOA exposure for several women participating in EuroMix. This calls for additional studies on exposure to PFOA and possibly other PFAS from PCPs, especially for women. Overall, PBPK modelling was shown as valuable tool in understanding the sources of PFOA exposure and in guiding risk assessments and regulatory decisions.

PFAS levels and determinants of variability in exposure in European teenagers - Results from the HBM4EU aligned studies (2014-2021).

BACKGROUND: Perfluoroalkyl substances (PFAS) are man-made fluorinated chemicals, widely used in various types of consumer products, resulting in their omnipresence in human populations. The aim of this study was to describe current PFAS levels in European teenagers and to investigate the determinants of serum/plasma concentrations in this specific age group. METHODS: PFAS concentrations were determined in serum or plasma samples from 1957 teenagers (12-18 years) from 9 European countries as part of the HBM4EU aligned studies (2014-2021). Questionnaire data were post-harmonized by each study and quality checked centrally. Only PFAS with an overall quantification frequency of at least 60% (PFOS, PFOA, PFHxS and PFNA) were included in the analyses. Sociodemographic and lifestyle factors were analysed together with food consumption frequencies to identify determinants of PFAS exposure. The variables study, sex and the highest educational level of household were included as fixed factors in the multivariable linear regression models for all PFAS and each dietary variable was added to the fixed model one by one and for each PFAS separately. RESULTS: The European exposure values for PFAS were reported as geometric means with 95% confidence intervals (CI): PFOS [2.13 µg/L (1.63-2.78)], PFOA ([0.97 µg/L (0.75-1.26)]), PFNA [0.30 µg/L (0.19-0.45)] and PFHxS [0.41 µg/L (0.33-0.52)]. The estimated geometric mean exposure levels were significantly higher in the North and West versus the South and East of Europe. Boys had significantly higher concentrations of the four PFAS compared to girls and significantly higher PFASs concentrations were found in teenagers from households with a higher education level. Consumption of seafood and fish at least 2 times per week was significantly associated with 21% (95% CI: 12-31%) increase in PFOS concentrations and 20% (95% CI: 10-31%) increase in PFNA concentrations as compared to less frequent consumption of seafood and fish. The same trend was observed for PFOA and PFHxS but not statistically significant. Consumption of eggs at least 2 times per week was associated with 11% (95% CI: 2-22%) and 14% (95% CI: 2-27%) increase in PFOS and PFNA concentrations, respectively, as compared to less frequent consumption of eggs. Significantly higher PFOS concentrations were observed for participants consuming offal (14% (95% CI: 3-26%)), the same trend was observed for the other PFAS but not statistically significant. Local food consumption at least 2 times per week was associated with 40% (95% CI: 19-64%) increase in PFOS levels as compared to those consuming local food less frequently. CONCLUSION: This work provides information about current levels of PFAS in European teenagers and potential dietary sources of exposure to PFAS in European teenagers. These results can be of use for targeted monitoring of PFAS in food.

Approaches to mixture risk assessment of PFASs in the European population based on human hazard and biomonitoring data.

Per- and polyfluoroalkyl substances (PFASs) are a highly persistent, mobile, and bioaccumulative class of chemicals, of which emissions into the environment result in long-lasting contamination with high probability for causing adverse effects to human health and the environment. Within the European Biomonitoring Initiative HBM4EU, samples and data were collected in a harmonized way from human biomonitoring (HBM) studies in Europe to derive current exposure data across a geographic spread. We performed mixture risk assessments based on recent internal exposure data of PFASs in European teenagers generated in the HBM4EU Aligned Studies (dataset with N = 1957, sampling years 2014-2021). Mixture risk assessments were performed based on three hazard-based approaches: the Hazard Index (HI) approach, the sum value approach as used by the European Food Safety Authority (EFSA) and the Relative Potency Factor (RPF) approach. The HI approach resulted in the highest risk estimates, followed by the RPF approach and the sum value approach. The assessments indicate that PFAS exposure may result in a health risk in a considerable fraction of individuals in the HBM4EU teenager study sample, thereby confirming the conclusion drawn in the recent EFSA scientific opinion. This study underlines that HBM data are of added value in assessing the health risks of aggregate and cumulative exposure to PFASs, as such data are able to reflect exposure from different sources and via different routes.

PFAS levels and exposure determinants in sensitive population groups.

BACKGROUND: Per- and polyfluoroalkyl substances (PFAS) are persistent organic pollutants. The first exposure to PFAS occurs in utero, after birth it continues via breast milk, food intake, environment, and consumer products that contain these chemicals. Our aim was to identify determinants of PFAS concentrations in sensitive population subgroups- pregnant women and newborns. METHODS: Nine European birth cohorts provided exposure data on PFAS in pregnant women (INMA-Gipuzkoa, Sabadell, Valencia, ELFE and MoBa; total N = 5897) or newborns (3xG study, FLEHS 2, FLEHS 3 and PRENATAL; total N = 940). PFOS, PFOA, PFHxS and PFNA concentrations were measured in maternal or cord blood, depending on the cohort (FLEHS 2 measured only PFOS and PFOA). PFAS concentrations were analysed according to maternal characteristics (age, BMI, parity, previous breastfeeding, smoking, and food consumption during pregnancy) and parental educational level. The association between potential determinants and PFAS concentrations was evaluated using multiple linear regression models. RESULTS: We observed significant variations in PFAS concentrations among cohorts. Higher PFAS concentrations were associated with higher maternal age, primipara birth, and educational level, both for maternal blood and cord blood. Higher PFAS concentrations in maternal blood were associated with higher consumption of fish and seafood, meat, offal and eggs. In cord blood, higher PFHxS concentrations were associated with daily meat consumption and higher PFNA with offal consumption. Daily milk and dairy consumption were associated with lower concentrations of PFAS in both, pregnant women and newborns. CONCLUSION: High detection rates of the four most abundant PFAS demonstrate ubiquitous exposure of sensitive populations, which is of concern. This study identified several determinants of PFAS exposure in pregnant women and newborns, including dietary factors, and these findings can be used for proposing measures to reduce PFAS exposure, particularly from dietary sources.

Per- and polyfluoroalkyl substances in serum and associations with food consumption and use of personal care products in the Norwegian biomonitoring study from the EU project EuroMix.

BACKGROUND: Human exposure to chemicals through the oral, dermal, or inhalation routes is significant. To assess this exposure, a human biomonitoring study was conducted in Norway to examine the plausibility of source-to-dose calculations for chemical mixtures. Per- and polyfluoroalkyl substances (PFASs) are man-made compounds used for their surfactant properties, and several are persistent and bioaccumulative. Some PFASs are toxic and are regarded as endocrine disruptors and have been shown to suppress immune function and affect cholesterol homeostasis. Using the participants from the EuroMix BM study, we set out to describe PFAS concentrations and to evaluate associations with diet and use of personal care products (PCPs). METHODS: Participants (44 males and 100 females) kept detailed diaries on their food consumption and their PCP use for two non-consecutive days. All urine (24 h) and blood samples were collected at the end of each study day. Levels of 25 PFASs were analysed in serum from study day 1 using a high throughput online solid phase extraction ultra-high-performance liquid chromatography tandem mass spectrometry method. Multivariable linear regressions were performed between each food and PCP category and each chemical and were sex-stratified when the consumption of food or use of PCPs was significantly different between men and women. RESULTS: Eight PFASs were detected in all analysed samples (PFHxS, PFHpS, PFOS, PFOA, PFNA, PFDA, PFUnDA and PFDoDA), and four PFASs were below the limit of detection (PFOPA, PFDPA, PFHxA, and EtFOSA). Several PFASs were found to be positively associated with fish consumption (PFOS, PFNA, PFUnDA, PFDoDA, PFDA, PFDS and PFTrDA). Sunscreen, mouthwash, and lip gloss/lip balm were found to be positively associated with PFASs (PFOA, PFTrDA, and PFOSA). CONCLUSION: The participants in the EuroMix study were exposed to PFASs through their diet and PCP use. Several foods and PCPs were found to be potential sources of exposure to PFASs.

Perfluoroalkyl substances, airways infections, allergy and asthma related health outcomes - implications of gender, exposure period and study design.

INTRODUCTION: Exposure to perfluoroalkyl substances (PFASs) has been inconsistently associated with asthma, allergic diseases and airways infections in early childhood. The aim of the study was, therefore, to investigate the effect of childhood exposure to PFASs on asthma and allergy related outcomes and on airways infections before and during puberty using the prospective birth cohort Environment and Childhood Asthma (ECA) Study. Aspects of gender, exposure period and study design (cross-sectional and longitudinal) were also taken into consideration. MATERIAL AND METHODS: Included in the study was 378 participants with PFAS measurements at age 10 years and follow-up data at ages 10 years (cross sectional data) and 16 years (longitudinal data). Eight PFASs with at least 70% of measurements above the limit of quantification (LOQ) in the child's serum were included in the present study: perfluoroheptanoate (PFHpA), perfluorooctanoate (PFOA), perfluourononanoate (PFNA), perfluorodecanoate (PFDA), perfluoroundecanoate (PFUnDA), perfluorohexane sulfonate (PFHxS), perfluoroheptane sulfonate (PFHpS) and perfluorooctane sulfonate (PFOS). The PFAS levels were converted into interquartile range (IQR). In addition, perfluorooctane sulfonamide (PFOSA) detected in 60% of the samples, was recoded into "not detected /detected". Binomial, multinomial and linear regression were used, followed by Bonferroni adjustment to correct for multiple comparisons. Sensitivity analyses evaluating the effect of extreme PFAS values and gender were performed. RESULTS: In the cross sectional data at 10 years a positive statistically significant association was seen between PFHpA and asthma in girls. In the longitudinal data, PFNA, PFDA and PFUnDA were inversely associated with atopic dermatitis (AD) in girls and with PFHxS in all participants and in boys. Further, PFNA and PFHpS were positively associated with rhinitis in girls and with PFOA in all participants. There seems to be a suggestive pattern of increased risk of allergic sensitisation in all participants and a decreased risk in boys, but due to different results in main and sensitivity analyses these findings should be interpreted with caution. No associations were found between PFASs and lung function. For airways infections and longitudinal data, PFDA was inversely associated with common cold, while positive association was found for PFHpA, PFOA, PFHpS and PFOS and lower respiratory tract infections (LRTI). DISCUSSION AND CONCLUSION: Our results lend further support for an immunosuppressive effect of PFASs on AD and LRTI. Gender seems to be important for some exposure-health associations. No clear pattern in exposure-health associations was observed with regard to exposure period or study design, with the exception of asthma where significant findings have mostly been reported in cross-sectional studies.

Neoadjuvant immunotherapy with combined ipilimumab and nivolumab in patients with melanoma with primary or in transit disease.

The introduction of new therapeutic agents has revolutionized the treatment of metastatic melanoma. The approval of adjuvant anti-programmed death-1 monotherapy with nivolumab or pembrolizumab, and dabrafenib plus trametinib has recently set a new landmark in the treatment of stage III melanoma. Now, clinical trials have shown that immune checkpoint blockade can be performed in a neoadjuvant setting, an approach established as a standard therapeutic approach for other tumour entities such as breast cancer. Recent studies suggest that a pathological response achieved by neoadjuvant immunotherapy is associated with long-term tumour control and that short neoadjuvant application of checkpoint inhibitors may be superior to adjuvant therapy. Most recently, neoadjuvant ipilimumab plus nivolumab in stage III melanoma was reported. With two courses of dose-optimized ipilimumab (1 mg kg-1 ) combined with nivolumab (3 mg kg-1 ), pathological responses were observed in 77% of patients, while only 20% of patients experienced grade 3 or 4 adverse events. However, the neoadjuvant trials employing combined immune checkpoint blockade conducted so far have excluded patients with in transit metastases, a common finding in stage III melanoma. Here we report four patients with in transit metastases or an advanced primary tumour who have been treated with neoadjuvant ipilimumab plus nivolumab according to the OpACIN-neo trial scheme (arm B). All patients achieved radiological disease control and a pathological response. None of the patients has relapsed so far. Linked Comment: Blankenstein and van Akkooi. Br J Dermatol 2020; 183:421-422.

Maternal levels of perfluoroalkyl substances (PFASs) during pregnancy and childhood allergy and asthma related outcomes and infections in the Norwegian Mother and Child (MoBa) cohort.

INTRODUCTION: Prenatal exposure to perfluoroalkyl substances (PFASs) has been inconsistently associated with asthma and allergic diseases and increased number of infections in early childhood. We examined the association of PFASs measured in pregnancy with childhood asthma, allergies and common infectious diseases in a prospective pregnancy cohort followed to age 7 years. MATERIAL AND METHODS: Six PFASs (out of 19 measured) with at least 80% of measurements above the limit of quantification (LOQ) in maternal plasma during pregnancy in two subcohorts of the Norwegian Mother and Child Cohort Study (MoBa) were analyzed in relation to health outcomes: perfluorooctane sulfonic acid (PFOS), acid (PFOA), perfluorohexane sulfonic acid (PFHxS), perfluorononanoic acid (PFNA), perfluoroundecanoic acid (PFUnDA), and perfluoroheptane sulfonic acid (PFHpS). Follow-up questionnaires were completed at 3 years by 1270 women and at 7 years by 972 women among the 1943 with pregnancy questionnaire and PFAS measures. Health outcomes included parent reports of child's symptoms or doctor diagnosed asthma and allergic conditions at age 7 years and parent-reported frequency of various infections at 3 and 7 years of age. Logistic and Poisson regression were used. The false discovery rate was controlled at 5%. Sensitivity analyses on gender were performed. RESULTS: Among the allergy and asthma outcomes, a statistically significant inverse association was seen between PFUnDA concentrations and ever having atopic eczema in girls. PFUnDA also tended to be inversely associated with both wheeze and asthma. For infections from 0 to 3 and 6 to 7 years, 11 significant positive associations were seen between PFASs and airways infections (bronchitis/pneumonia, throat infection, pseudocroup), ear infection and gastric flu/diarrhea; whereas 6 inverse associations were seen for pseudocroup, ear infections and urinary tract infections. The majority of the findings with respect to infectious diseases were found in girls only. DISCUSSION: With the exception of an inverse association between PFUnDA and eczema, and a tendency of a similar association for wheeze and asthma, maternal PFAS levels during pregnancy showed little association with asthma or allergy related outcomes. Findings from the present study suggest immunosuppressive effects of PFASs on airways infections, such as bronchitis/pneumonia and throat infections, as well as diarrhea/gastric flu. Our results indicate a possible role of gender in the PFAS-health outcome associations.

Prenatal exposure to perfluoralkyl substances (PFASs) associated with respiratory tract infections but not allergy- and asthma-related health outcomes in childhood.

BACKGROUND: Prenatal exposure to perfluoralkyl substances (PFASs) has been reported to be associated with immunosuppression in early childhood, but with contradictory findings related to atopic and lung diseases. AIM: We aimed to determine if prenatal exposure to PFASs is associated with asthma or other allergic diseases or respiratory tract infections in childhood. METHODS: Nineteen PFASs were measured in cord blood available from 641 infants in the Environment and Childhood Asthma (ECA) prospective birth cohort study. The six most abundant PFASs were perfluorooctane sulfonic acid (PFOS), perfluorooctanoic acid (PFOA), perfluorooctanesulfonamide (PFOSA), perfluorohexane sulfonic acid (PFHxS), perfluorononanoic acid (PFNA), and perfluoroundecanoic acid (PFUnDA). Health outcomes were assessed at two and ten years of age, and included reported obstructive airways disease (wheeze by 10 years; asthma by 2 and 10 years; reduced lung function at birth; allergic rhinitis by 10 years), atopic dermatitis (AD) by 2 and 10 years, allergic sensitization by 10 years, and episodes of common respiratory tract infections (common cold by 2 years, lower respiratory tract infections (LRTI) by 10 years). The associations between exposure and health outcomes were examined using logistic and Poisson regression. RESULTS: The number of reported airways infections were significantly associated with cord blood concentrations of PFAS; common colds by two years with PFUnDA (ß = 0.11 (0.08-0.14)) and LRTIs from 0 to 10 years of age with PFOS (ß = 0.50 (0.42-0.57)), PFOA (ß = 0.28 (0.22-0.35)), PFOSA (ß = 0.10 (0.06-0.14)), PFNA (ß = 0.09 (0.03-0.14)) and PFUnDA (ß = 0.18 (0.13-0.23)) concentrations. Neither reduced lung function at birth, asthma, allergic rhinitis, AD nor allergic sensitization were significantly associated with any of the PFASs. CONCLUSION: Although prenatal exposure to PFASs was not associated with atopic or lung manifestations by 10 years of age, several PFASs were associated with an increased number of respiratory tract infections in the first 10 years of life, suggesting immunosuppressive effects of PFASs.

Improved technical success, postnatal outcome and refined predictors of outcome for fetal aortic valvuloplasty.

OBJECTIVES: Fetal aortic valvuloplasty (FAV) may prevent progression of mid-gestation aortic stenosis to hypoplastic left heart syndrome (HLHS). The aim of this study was to evaluate whether technical success and biventricular (Biv) outcome after FAV have changed from an earlier (2000-2008) to a more recent (2009-2015) era and identify pre-FAV predictors of Biv outcome. METHODS: We evaluated procedural and postnatal outcomes in 123 fetuses that underwent FAV for evolving HLHS at Boston Children's Hospital between 2000 and 2015. The primary outcome measure was circulation type (Biv vs single ventricle) at the time of neonatal hospital discharge. Classification and regression tree (CART) analysis was performed to construct a stratification algorithm to predict Biv circulation based on pre-FAV fetal variables. RESULTS: The FAV procedure was technically successful in 101/123 (82%) fetuses, with a higher technical success rate in the more recent era than in the earlier one (49/52 (94%) vs 52/71 (73%); P = 0.003). In liveborn patients, the incidence of Biv outcome was higher in the recent than in the earlier era, both in the entire liveborn cohort (29/49 (59%) vs 16/62 (26%); P = 0.001) and in those in whom the procedure was technically successful (27/46 (59%) vs 15/47 (32%); P = 0.007). Independent predictors of Biv outcome were higher left ventricular (LV) pressure, larger ascending aorta, better LV diastolic function and higher LV long-axis Z-score. On CART analysis, fetuses with LV pressure > 47 mmHg and ascending aorta Z-score ≥ 0.57 had a 92% probability of Biv outcome (n = 24). Those with a lower LV pressure, or mitral dimension Z-score < 0.1 and mitral valve inflow time Z-score < -2 (n = 34) were unlikely to have Biv (probability of 9%). The remainder of the patients had an intermediate (∼40-60%) likelihood of Biv circulation. CONCLUSIONS: The proportion of patients achieving Biv outcome after FAV has increased, probably owing to an improved technical success rate and modified selection criteria. Fetal factors, including LV pressure, size of the ascending aorta and diastolic function, are associated with likelihood of Biv circulation after FAV. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

Should embryos with autosomal monosomy by preimplantation genetic testing for aneuploidy be transferred?: Implications for embryo selection from a systematic literature review of autosomal monosomy survivors.

OBJECTIVE: To review the literature for survival and phenotypes of liveborns with autosomal monosomy to inform decisions regarding transfer of in vitro fertilization-derived embryos reported as monosomic on preimplantation genetic testing for aneuploidy (PGT-A). METHOD: Ovid-Medline and EMBASE were systematically searched to identify published case reports of liveborn individuals with autosomal monosomy, full or mosaic, for a whole chromosome. RESULTS: Fifty-three reports describing 56 individuals with autosomal monosomy met the selection criteria: 1 case each of monosomy 14 and 16, 3 each for monosomy 15 and 18, 1 for group "E", 5 for monosomy 20, 24 for monosomy 21, 7 for monosomy 22, and eleven for a "G" group chromosome. There were no reports with monosomy for the larger chromosomes 1 through 13, nor for chromosomes 17 or 19, autosomes with highest gene density. Most reported individuals had severe handicaps and died in infancy with some surviving longer. CONCLUSION: Given potential for survival of handicapped individuals with autosomal monosomy for chromosomes 14, 15, 16, 18, 20, 21, and 22, low priority should be given to transfer of embryos apparently monosomic for these chromosomes. Couples electing transfer of monosomic embryos should consider amniocentesis for ongoing pregnancies but should be informed of its limitations.

Confined placental mosaicism for 22q11.2 deletion as the etiology for discordant positive NIPT results.

22q11.2 deletion, the most common microdeletion syndrome within the general population, is estimated to have a prevalence of 1 in 3000 to 6000. Non-invasive prenatal testing has recently expanded to include screening for several microdeletions including 22q11.2. Given the expansion of prenatal screening options to include microdeletions, it is important to understand the limits of this technology and the variety of reasons that a discordant positive result can occur. Here, we describe a case of a pregnant woman who received a positive non-invasive prenatal maternal plasma screen for 22q11.2 deletion. Maternal and postnatal neonatal peripheral blood cytogenetic, PCR, and fluorescence in situ hybridization studies were normal, but the placenta was mosaic for 22q11.2 deletion in two of three biopsy sites. This case illustrates both the complexities of pre- and post-test counseling for microdeletion screening and the potential for a discordant positive microdeletion result because of confined placental mosaicism. © 2017 John Wiley & Sons, Ltd.

Perfluoroalkyl substances measured in breast milk and child neuropsychological development in a Norwegian birth cohort study.

Perfluoroalkyl substances (PFASs) are chemicals with potential neurotoxic effects although the current evidence is still limited. This study investigated the association between perinatal exposure to perfluorooctanesulfonic acid (PFOS) and perfluorooctanoic acid (PFOA) and neuropsychological development assessed at 6, 12 and 24 months. We measured PFOS and PFOA in breast milk samples collected one month after delivery by mothers of children participating in the HUMIS study (Norway). Cognitive and psychomotor development was measured at 6 and at 24 months using the Ages and Stages Questionnaire (ASQ-II). Behavioral development was assessed using the infant-toddler symptom checklist (ITSC) at 12 and at 24 months. Weighted logistic regression and weighted negative binomial regression models were applied to analyze the associations between PFASs and ASQ-II and ITSC, respectively. The median concentration of PFOS was 110 ng/L, while the median for PFOA was 40 ng/L. We did not detect an increased risk of having an abnormal score in ASQ-II at 6 months or 24 months. Moreover, no consistent increase in behavioral problems assessed at 12 and 24 months by ITSC questionnaire was detected. We observed no association between perinatal PFOS and PFOA exposure and early neuropsychological development. Further longitudinal studies are needed to confirm the effects of these compounds on neuropsychological development in older children.

The effect of obstetric practice change to reduce early term delivery on perinatal outcome.

OBJECTIVE: To investigate whether the national emphasis on attaining 39 weeks gestation has altered obstetric practice, and if so whether this has affected perinatal morbidity. STUDY DESIGN: We examined trends in gestational age, neonatal morbidity, maternal complications and stillbirth for a retrospective cohort of singleton, live births between 37+0 and 39+6 weeks of gestation over a 5-year period at a single tertiary care center. RESULT: There were 21 343 eligible deliveries. The proportion of deliveries in the early term (<39 weeks) decreased from 47.8 to 40.2% (P<0.01). The reduction was most pronounced for elective inductions (27.5 to 8.0%; P<0.01) and scheduled cesareans (56.9 to 24.9%; P<0.01), although a similar trend was seen for nonelective inductions (51.2 to 47.9%; P=0.03). In multivariable analysis, there was a 10% decreased odds of early term delivery per year (P<0.01). There were no changes in the rates of neonatal intensive care unit (NICU) evaluation (29.8 to 28.1%; P=0.11), pre-eclampsia (7.6 to 8.5%; P=0.06) or stillbirth (11.5 to 14.4 per 10 000; P=0.55). CONCLUSION: A 10% annual decline in the odds of early term delivery was not accompanied by significant changes in perinatal morbidity.

Review: cell-free fetal DNA in the maternal circulation as an indication of placental health and disease.

In human pregnancy, the constant turnover of villous trophoblast results in extrusion of apoptotic material into the maternal circulation. This material includes cell-free (cf) DNA, which is commonly referred to as "fetal", but is actually derived from the placenta. As the release of cf DNA is closely tied to placental morphogenesis, conditions associated with abnormal placentation, such as preeclampsia, are associated with high DNA levels in the blood of pregnant women. Over the past five years, the development and commercial availability of techniques of massively parallel DNA sequencing have facilitated noninvasive prenatal testing (NIPT) for fetal trisomies 13, 18, and 21. Clinical experience accrued over the past two years has highlighted the importance of the fetal fraction (ff) in cf DNA analysis. The ff is the amount of cell-free fetal DNA in a given sample divided by the total amount of cell-free DNA. At any gestational age, ff has a bell-shaped distribution that peaks between 10 and 20% at 10-21 weeks. ff is affected by maternal body mass index, gestational age, fetal aneuploidy, and whether the gestation is a singleton or multiple. In approximately 0.1% of clinical cases, the NIPT result and a subsequent diagnostic karyotype are discordant; confined placental mosaicism has been increasingly reported as an underlying biologic explanation. Cell-free fetal DNA is a new biomarker that can provide information about the placenta and potentially be used to predict clinical problems. Knowledge gaps still exist with regard to what affects production, metabolism, and clearance of feto-placental DNA.

Long-term effects of prenatal exposure to perfluoroalkyl substances on female reproduction.

STUDY QUESTION: Does prenatal exposure to perfluoroalkyl substances (PFASs) have long-term effects on female reproductive function?. SUMMARY ANSWER: Our results suggest an association between in utero exposure to perfluorooctanoic acid (PFOA) and delay in age of menarche. WHAT IS KNOWN ALREADY: Previous cross-sectional studies have reported possible effects of PFASs on female reproduction including reduced fecundity, delayed puberty and accelerated age at menopause. Only limited data exist from follow-up studies on long-term implications of prenatal exposure to PFASs. STUDY DESIGN, SIZE, DURATION: In this study we used data from a Danish population-based cohort established in 1988-1989. Of 1212 eligible pregnant women, 965 participated. Follow-up was initiated in 2008 on the female offspring at ∼20 years of age. Three hundred and sixty seven (84%) daughters answered a questionnaire and 267 (61%) daughters furthermore attended clinical examinations which were conducted in 2008-2009. PARTICIPANTS/MATERIALS, SETTING, METHODS: The final study population consisted of 343 daughters of which 254 had attended the clinical examinations and 89 had answered the questionnaire only. Levels of PFASs in maternal serum from pregnancy week 30 were used as a measure of prenatal exposure and related to age of menarche, menstrual cycle length, levels of reproductive hormones and follicle number of the daughters. Data were divided into three groups according to tertiles of maternal concentrations of PFASs (low, medium, high). MAIN RESULTS AND THE ROLE OF CHANCE: In adjusted regression analyses, daughters exposed to higher levels of PFOA in utero had a 5.3 (95% confidence interval: 1.3; 9.3) months later age of menarche compared with the reference group of lower PFOA. Crude (P = 0.05) and adjusted (P = 0.01) trend tests also indicated a relationship between higher prenatal PFOA exposure and delay of menarche. LIMITATIONS, REASONS FOR CAUTION: We did not measure the exact amount of PFASs to which the daughters had been exposed prenatally. Instead we used PFAS concentrations in maternal serum as surrogates. However, PFASs are efficiently transferred to the fetus via placenta. Information on age of menarche was collected retrospectively but the time interval for recall in our study was relatively short (2-10 years). The remaining outcome measures depended on participation in clinical examination which reduced the number of observations leading to limited statistical power and risk of selection bias. WIDER IMPLICATIONS OF THE FINDINGS: Since PFASs can be detected in humans all over the world, effects of prenatal exposure on female reproductive function later in life may have wide health implications. STUDY FUNDING/COMPETING INTEREST(S): The study was supported by the Danish Council for Independent Research (271-05-0296, 09-065631), the Danish Ministry of Interior and Health (0-302-02-18/5), the Danish Council for Strategic Research (09-067124 (Centre for Fetal Programming), 09-063072, 2101-06-0005), the Novo Nordisk Foundation, the Aarhus University Research Foundation, the Frimodt-Heineke Foundation, the Foundation of Maria Dorthea and Holger From, the Beckett-Foundation, the Research Grant of Organon and the Foundation of Lily Benthine Lund. There are no competing interests. TRIAL REGISTRATION NUMBER: Not applicable.

A new radiological method to detect dorsally penetrating screws when using volar locking plates in distal radial fractures. The dorsal horizon view.

Penetration of the dorsal screw when treating distal radius fractures with volar locking plates is an avoidable complication that causes lesions of the extensor tendon in between 2% and 6% of patients. We examined axial fluoroscopic views of the distal end of the radius to observe small amounts of dorsal screw penetration, and determined the ideal angle of inclination of the x-ray beam to the forearm when making this radiological view. Six volar locking plates were inserted at the wrists of cadavers. The actual screw length was measured under direct vision through a dorsal approach to the distal radius. Axial radiographs were performed for different angles of inclination of the forearm at the elbow. Comparing axial radiological measurements and real screw length, a statistically significant correlation could be demonstrated at an angle of inclination between 5° and 20°. The ideal angle of inclination required to minimise the risk of implanting over-long screws in a dorsal horizon radiological view is 15°.

[Secondary reconstruction of the digital A2-flexor pulley]. / Sekundäre Rekonstruktion des digitalen A2-Ringbands.

OBJECTIVE: Secondary reconstruction of A2 flexor pulley for after closed rupture. INDICATIONS: Persisting impairment of finger function and strength after combined injury of A2 and C1 pulley. Passive free movement of all finger joints. CONTRAINDICATIONS: Fixed flexion contractures of interphalangeal joints after complex finger injuries. Degenerative arthrosis of interphalangeal joints. SURGICAL TECHNIQUE: A strip of extensor retinaculum approximately 10 mm in width together with the periosteum from the second floor of the extensor tunnel was used for reconstruction of the A2 pulley. After drilling bilateral burr holes in the palmar aspect of the phalanx at the distal and proximal ends of the A2 pulley, the graft was fixed by the periosteum to the bone of the phalanx, placing the synovial layer innermost. POSTOPERATIVE MANAGEMENT: Postoperatively, patients in both treatment groups wore a palmar splint which extended from the distal interphalangeal joint to the proximal palmar crease for 4 weeks. The metacarpophalangeal joint and the proximal interphalangeal joint were held in full extension. After removing the splint, physiotherapy was started. Full load-bearing, hard manual work and sport activities were not permitted for 3 months. RESULTS: Fifteen patients were treated using the extensor retinaculum for reconstruction of the A2 flexor pulley. The mean follow-up time was 48 months. The average range of motion of the PIP joint was 97 %, the average power grip strength 96 %, the finger pinch strength 100 %, and the average circumference 95 % of the uninjured contralateral side. The Buck-Gramcko score showed the following results: 10 excellent, 2 good, and 1 fair.

Determinants of plasma concentrations of perfluoroalkyl substances in pregnant Norwegian women.

BACKGROUND: Perfluoroalkyl substances (PFASs) are widespread pollutants that have been associated with adverse health effects although not on a consistent basis. Diet has been considered the main source of exposure. The aim of the present study was to identify determinants of four plasma PFASs in pregnant Norwegian women. METHODS: This study is based in the Norwegian Mother and Child Cohort Study (MoBa) conducted by the Norwegian Institute of Public Health. Our sample included 487 women who enrolled in MoBa from 2003 to 2004. A questionnaire regarding sociodemographic, medical, and reproductive history was completed at 17 weeks of gestation and a dietary questionnaire was completed at 22 weeks of gestation. Maternal plasma samples were obtained around 17 weeks of gestation. Plasma concentrations of four PFASs (perfluorooctane sulfonate (PFOS), perfluorooctanoate (PFOA), perfluorohexane sulfonate (PFHxS), and perfluorononanoate (PFNA)) were examined in relation to demographic, lifestyle, dietary, and pregnancy-related covariates. Predictors were identified by optimizing multiple linear regression models using Akaike's information criterion (AIC). RESULTS: Parity was the determinant with the largest influence on plasma PFAS concentrations, with r(2) between 0.09 and 0.32 in simple regression models. In optimal multivariate models, when compared to nulliparous women, parous women had 46%, 70%, 19%, and 62% lower concentrations of PFOS, PFOA, PFHxS, and PFNA respectively (p<0.001 except for PFHxS, p<0.01). In all these models, duration of breastfeeding was associated with reduced PFAS levels. PFOA showed the largest reduction from breastfeeding, with a 2-3% reduction per month of breastfeeding in typical cases. Levels of PFOS, PFOA, and PFNA increased with time since most recent pregnancy. While pregnancy-related factors were the most important predictors, diet was a significant factor explaining up to 4% of the variance. One quartile increase in estimated dietary PFAS intake was associated with plasma PFOS, PFOA, PFHxS, and PFNA concentration increases of 7.2%, 3.3%, 5.8% and 9.8%, respectively, resulting in small, although non-trivial absolute changes in PFAS concentrations. CONCLUSION: Previous pregnancies and breastfeeding duration were the most important determinants of PFASs in this sample of pregnant women.